Coccidioides species (C. immitis and C. posadasii) are the causative agents of coccidioidomycosis (Valley Fever), an important emerging disease endemic to the southwestern US as well as parts of Mexico and central and South America. Infection begins with inhalation of arthroconidia that initiate the parasitic phase in lungs and can result in a respiratory infection or if not controlled, a more serious disseminated disease.
Coccidioides spp. are dimorphic and produce a unique parasitic phase structure, the spherule, via a switch from polar to isotrophic growth with the spherule expanding from a barrel-shaped arthrocondium that is 3-6 μm by 2-4 μm in size to a sphere 80-100 microns in diameter. Internal septation and spore formation results in production of hundreds of endospores that if released can disseminate and reinitiate spherule formation at other places in the body. Most infections are mild and resolve without medical intervention although about 30% of infections cause flu-like symptoms that may take 1-4 months to resolve.
A variety of approaches have been used to understand genes important for the parasitic phase of these and other fungi. These include random mutagenesis, targeted disruption of parasitic phase-specific genes and targeted mutagenesis of genes identified in other pathogens as virulence factors. In addition, expression analyses have been performed to identify phase-specific or phase-induced genes. For Coccidioides, both expression analyses and the latter two mutagenesis approaches have been used, resulting in a number of mutants, some of which are altered in virulence. For example, SOWgp and MEP1 have been knocked out and the resulting mutant strains are reduced in virulence.
Over the last 50 years, many approaches to vaccination against coccidioidomycosis have been tried, including whole killed cells, live mutant vaccines that have been modified in virulence, partially purified cellular extracts, and recombinant proteins that were identified by a myriad of both low and high technology methods. To date, killed whole cell vaccines provide the best protection in mice but are not transferable to humans because of intolerable adverse effects and poor efficacy. Recombinant proteins offer the safest approach but have modest efficacy in mice and have not been tried in a higher species.